Recently, as a drug delivery material for improving circulation in blood of pharmaceuticals and physiologically active substances and imparting a targeting function toward a target site, a polyalkylene glycol derivative has been utilized. Since more improved circulation in blood is observed as the molecular weight of a polyalkylene glycol increases, a polyalkylene glycol derivative having a molecular weight of thousands or more has been frequently used. Moreover, as a functional group to be utilized for binding to drugs, an aldehyde group has excellent characteristic features that it forms a Schiff base with a primary amine and forms a more stable secondary amine through reductive amination and also the shift of isoelectric point is small since the secondary amine is present even after the binding. Furthermore, in the case where a pharmaceutical to be a target is a protein, since an aldehyde group can be bound to an N-terminal amine group depending on reaction conditions, an aldehyde group is also excellent in view of selectivity of binding site. Therefore, a polyalkylene glycol derivative having an aldehyde group has been widely used for binding to pharmaceuticals having an amino group. As a commercially available example of pharmaceutical modification of the polyalkylene glycol derivative having an aldehyde group, there is mentioned a pharmaceutical in which granulocyte colony-stimulating factor (G-CSF) is modified with a polyalkylene glycol derivative having a molecular weight of 20,000, and the pharmaceutical has gained a large sales. Currently, development of generic drugs, application to the other pharmaceuticals, and the like have been actively investigated and thus there is an increasing demand for the polyalkylene glycol derivative having an aldehyde group.
As methods for synthesizing the polyalkylene glycol derivative having an aldehyde group, there are following two manufacturing methods. In the first method, after the hydroxyl group of an acetal compound having a hydroxyl group is converted into an alcoholate or the like to enhance reactivity and then bound to a polyalkylene glycol terminal, the acetal group is hydrolyzed to synthesize a terminal aldehyde compound. In the second method, after an alkylene oxide is addition-polymerized to the hydroxyl group of an acetal compound having a hydroxyl group under an alkali catalyst, the acetal group is hydrolyzed. In both methods, as a raw material for the polyalkylene glycol derivative having an aldehyde group, there is employed a compound having an acetal group that is a protective group of aldehyde and a hydroxyl group in the molecule.
When a reactive impurity having a hydroxyl group is present in the acetal compound raw material, the impurity is converted into a polyalkylene glycol derivative other than the objective compound in each method, through binding of the impurity to the polyalkylene glycol derivative in the former method or through addition polymerization of the alkylene oxide in the latter method. When such an impurity remains, purity of the pharmaceuticals decreases and also it may be a main cause of inducing heterogeneity and performance inhibition, resulting in a serious problem.
As a difference between the impurity having a polyalkylene glycol structure formed as a by-product and the polyalkylene glycol derivative having an aldehyde group as an objective compound, a terminal structure is slightly different from each other within the molecular weight of several thousands to several tens of thousands. Therefore, chemical properties are similar and thus it is very difficult to purify the polyalkylene glycol derivative. In a high molecular weight range where the circulation in blood is improved, the property difference from the objective compound further decreases, so that purification becomes difficult. Moreover, since such a reactive substituent as an aldehyde group is present, there is rather a possibility that a side reaction may be induced to lower the purity depending on a purification operation. For the above reasons, in order to manufacture a highly pure polyalkylene glycol derivative, it is necessary to manufacture the acetal compound, which is a raw material for the polyalkylene glycol derivative, in high purity.
As the reactive impurity in the acetal compound having a hydroxyl group as a raw material, a polyacetal, an alcohol, and an antioxidant may be mentioned.
With regard to the polyacetal, since an acetal group is generally prone to undergo decomposition by heat, the polyacetal is formed as a by-product through intermolecular acetal exchange. The alcohol is formed as a by-product through elimination of the alcohol that has formed the acetal group at the above polyacetalization. With regard to the antioxidant, the following contamination mechanism may be present other than the addition thereof for the purpose of improving stability of the objective compound. For example, in Non-Patent Document 1 (ACTA CHEMICA SCANDINAVIA 27 (1973) 239-250), an acetal compound having an ethyl ester is reduced with lithium aluminum hydride to synthesize the acetal compound having a hydroxyl group. In the reduction reaction, an ether solvent is generally employed. Usually, an aliphatic ether such as diethyl ether or tetrahydrofuran to be used as the ether solvent is added with an antioxidant such as 2,6-di-tert-butyl-p-cresol (BHT) for the purpose of preventing the solvent from being oxidized with oxygen to form a peroxide. Thus, when the ether solvent is used for the synthesis, BHT is entrained.
These three kinds of impurities are entrained in the methods for manufacturing the acetal compound having a hydroxyl group, which have hitherto been reported. For example, as an example where the acetal compound having a hydroxyl group is bound to a polyalkylene glycol derivative, in Patent Document 1 (US2005/0176896 A1), after 3,3-diethoxy-1-propanal is subjected to azeotropic dehydration in toluene, it is converted into an alcoholate and then bound to the polyalkylene glycol derivative. In this method, impurities having a hydroxyl group, such as a polyacetal and BHT, which have a boiling point higher than that of toluene, remain.
Moreover, as an example where an alkylene oxide is addition-polymerized to an acetal compound having a hydroxyl group, Non-Patent Document 2 (Macromolecules 2000, 33, 5841-5845) may be mentioned. In the Document, 3,3-diethoxy-1-propanol is distilled and there is a problem that BHT that is a subliming substance is sublimed and thus coexists with the objective compound and a polyalkylene glycol derivative having a BHT structure at the terminal is formed as a by-product.